Solidified drug supply for generating inhalable drug particles

ABSTRACT

A solidified drug supply for generating inhalable drug particles with the aid of a metering device includes a removal unit, with the drug supply being brittle and textureless. The density and the mechanical strength of the drug supply is abraded everywhere in such a way that the structure of the material removed from one side of the drug supply by the metering device is uniform across the entire usage region in the direction of the removal.

BACKGROUND OF THE INVENTION

The present invention relates to a solidified drug supply for generatinginhalable drug particles with the aid of a metering device comprisingremoval means.

Drug supplies of this type are known from WO 93/24165 and are used inaerosol generators having a metering device which includes removalmeans, for example, in the form of a driven face cutter, for removingdrug particles from the drug supply and generating an aerosol which isreleased for oral or nasal inhalation at the instant when it isgenerated.

From DE 40 27 390 A1 there is known an inhalation device wherein a brushis used to remove dust-like particles from a tablet wherein thegeometrical form of the tablet may vary.

EP 040702882 also describes an aerosol generator having a pressed bodyof an inhalable drug. The pressure suggested for pressing the drugsupply is a so-called lightly densified pressure range between 1×10⁴ to15×10⁴ N/m² as well as a strongly densified pressure range between30×10⁴ and 150×10⁴ N/m². However, even this higher pressure range is setto such a low value that the manageable structure can only exist becausethe drug supply is pressed into a cylindrical container and is heldtogether by that container. Since the drug supply is not compacted verydensely, a homogeneous pressure distribution in the bulk of the drugmaterial is not achieved because of the internal friction effects in thebulk and because of the friction between the drug supply and thecontainer wall. As a result, drug supplies of this type exhibit densitygradients of more than 40% which have a negative effect on the meteringaccuracy (see also: B. Chariton and J. M. Newton, "Application of GammaRay Attenuation to the Determination of Density Distribution withinCompacted Powders", Powder Technology 41 (1985), 123 to 134).

Since according to a publication of the applicant of EP 0 407 028 A2,the densities of the drug supply are about 0.8 to 0.9 g/cm⁻³, the volumedensity for the densified drug supply is calculated to be about 50% ofthe theoretical density. Accordingly, such a highly porous drug supplyis not only very porous and inhomogeneous, but is, as a result of thelarge open porosity, also subjected to agglomeration and to aging causedby the atmospheric factors, such as humidity and the like.

A solidified drug supply is known from PCT/EP 93/00158, wherein thesignificance of structural and chemical homogeneity of the solidifieddrug supply for the metering accuracy pointed out. Therein, isostaticpressing is proposed for obtaining a proper structure; this pressing(molding) method is known from powder metallurgy when flexible forms areemployed. Herein, a batch of powder disposed, for instance, inside arubber form, is densified all around and therefore isostatically fromthe outside with the help of a pressure liquid. Also proposed in thispublication are other forming methods aside from isostatic pressing, forexample, injection molding of plastified materials.

Further investigations on solidified drug supplies have shown that thequality requirements with respect to structure are much higher than havebeen assumed previously. It has been found that during removal by ametering device comprising a removal means, such as known from WO93/24165, potential variations in density can have a significant effecton the generated amount of aerosol.

It was also observed that isostatically pressed drug supplies initiallyexhibit inexplicable dose variations at the removal end face, whichcould not be explained by density or material inhomogeneities measuredin the bulk. A more accurate investigation of these occurrences hasdemonstrated that defects in material, such as texturing andmicro-fissures, occur in these marginal regions whereby larger sectionsof material may chip off during removal, resulting in dosage variations.

It now appears that such defects in material are the result of theisostatic pressing process. Strictly speaking, an ideal isostaticpressure transmission to the powder material occurs only in forms ofspherical or nearly spherical geometry. If, however, the shape of theform deviates from the isometric form which is, for example, the casefor ring-shaped removal members for inhalation purposes, then thepressure transmission is no longer completely isostatic, but isdirectional. If, for example, such ring-shaped tablet for an inhalatoris isostatically pressed, then radial and axial forces are superposed inthe region of the end faces, wherein these forces cause texturing in thecritical regions of the end faces, in particular, since a form with thisshape exhibits a different stiffness with respect to the hydrostaticpressure and consequently a different deformability when the pressure isbuilding up. This causes an initial densification phase in radialdirection and a subsequent post-densification of the alreadypre-solidified powder material in axial direction which causes theaforementioned textures and micro-fissures in the structure of thering-shaped tablet. For the known applications of isostatic molding(pressing) in the field of powder metallurgy and ceramics, suchdevelopments usually are not important, since the resulting structuraldefects are annealed during the subsequent sintering process withoutleaving any blemishes. This possibility however, does not exist with adrug supply which is used without such post-treatment.

It has been found that the above-mentioned friction effects inside abulk powder material also occur when a drug supply is isostaticallypressed, however, not to such extent as with unidirectional pressingmethods. Even for an isostatic pressing operation, the pressure lossinside the bulk powder increases with the thickness of the form in thedirection facing the pressing force. Consequently, density gradientswithin the cylinder walls in radial and axial direction occur alsoduring isostatic pressing of a ring tablet, resulting in completelyformed zone of equal densities or textures, respectively, in the regionof the end face.

SUMMARY OF THE INVENTION

It is the object of the invention to provide a solidified drug supplywhich can be removed reproducibly over the entire usage region and whichproduces the desired particle uniformity.

The object of the invention is solved by a drug supply including asolidified body of medicament having a texture formed by applying apressing force from outside in a direction toward a core positionedcentrally in the solidified body. In particular, the solidified body hasa density and a mechanical strength is and so defined as to enable anabrasion everywhere in such a way that the structure of the materialremoved from one side of the drug supply by the metering device isuniform across the entire usage region in the direction of the removal.

The drug supply provided according to the invention may be disposed inan aerosol generator, like aerosol generator known from WO 93/24165 bythe present applicant. The device described in this publication isexplicitly referenced herein, and is incorporated into the presentapplication by reference. When the aerosol dose is removed by the facecutter operating in an axial direction, the drug supply of the inventionprovides a very small, but particularly coaxial density distributionwhich does not affect the generated amount of aerosol and the quantityof the aerosol.

In a preferred embodiment of the invention, the structure of the drugsupply may be generated by applying a pressing force in a directionessentially perpendicular to the direction of the subsequent removal.Surprisingly, this method of applying pressure--which is different fromisostatic pressing--results in excellent properties of the solidifieddrug supply. Since in this embodiment the pressing force is appliedexclusively in one direction, for example, radially, the densitygradient in the drug supply which is generated in this fashion, is alsodirected strictly radially due to the internal friction described above,i.e. the zones of equal density extend parallel and concentrically tothe longitudinal axis of the drug supply.

According to another embodiment of the invention, the drug supply mayhave a circular cross section and may be fabricated by applying thepressing.

The invention is particularly advantageous with ring-shaped tablets.Here too, a pressing force is essentially directed radially against astationary core.

As a result of this geometrical shape, a particularly advantageousstructure with minimum density gradients in radial and axial directionis attained when only the radial pressing force is applied. According toanother preferred embodiment of the invention, the density gradientperpendicular to the removal direction may be no larger than 0.3% and0.05% in the removal direction. It has not been possible until now torealize such small density gradients with drug supplies adapted forgenerating inhalable drug particles with a metering device. The drugsupply may be fabricated from a granulated carrier material-activeingredient mixture, wherein the pressing forces for the drug supply ofthe invention are between 50 and 500 MPa.

Another feature of the invention relates to a method for fabricating asolidified drug supply for generating inhalable drug particles with ametering device comprising removal means wherein a pressing force isapplied to the drug material. According to the invention, the pressingforce is here applied essentially in the direction perpendicular to thedirection of the subsequent removal wherein, according to a preferredembodiment, the pressing force in every direction perpendicular to thesubsequent removal direction is identical. With this fabrication method,the advantageous properties of an abovedescribed drug supply used forgenerating drug particles are attained.

Depending on the shape desired for the solidified drug supply, the drugsupply is pre-shaped when subjected to the pressing force. For a ringtablet, the drug material--either in powder form or pre-densified--isplaced around a stationary core and subsequently pressed against thecore by radial pressing force. The core is preferably removed after thepressing step and the ring tablet is taken out.

According to another preferred embodiment of the method, the drug supplyis initially formed as a rod-shaped body with, for example, a length of200 mm, and is subsequently separated perpendicular to its long axis.This method enables a particularly efficient fabrication of theplurality of drug supplies with the desired properties for use in acooperating aerosol generator.

Another feature of the invention relates to an apparatus for fabricatinga solidified drug supply by applying a pressing force to a drugmaterial. The apparatus of the invention comprises a press space formedby at least two parallel stationary plates separated in space and aflexible ram, wherein the faces of the plates and the ram facing thepress space are arranged perpendicular with respect to each other. Suchapparatus enables the fabrication of a drug supply with the desiredproperties in an easy and convenient manner.

According to a preferred embodiment, the press space may be a ring spaceformed about a cylindrical core, the ring space surrounded by theflexible ram, wherein the extrusion die, when subjected to pressure, ismoveable towards the core, thereby providing the exclusively radialpressing force.

BRIEF DESCRIPTION OF THE DRAWING

The invention will be described hereinafter with reference to theappended drawing, taking a preferred embodiment as an example. It isshown in:

FIG. 1 a schematic cross-sectional view of an apparatus for fabricatinga solidified drug supply without applied pressing force; and

FIG. 1a the apparatus of FIG. 1 with pressing force applied.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The press depicted in FIG. 1 for fabricating a solidified drug supply byapplying a pressing force to the drug material 9 comprises a press spaceformed by two parallel stationary and spaced apart plates 2 and aflexible ram 8. The faces of the plates 2 and the ram 8 facing the pressspace are arranged perpendicular with respect to each other. The outerhousing of the press chamber depicted in FIG. 1 is formed by an upperhousing plate and a lower housing plate 1 which is pressed firmly ontothe ring jacket 4 by the closing force of a hydraulic press (not shown).The closing force of the hydraulic press is significantly higher thanthe oil pressure acting on the ram inside the press chamber so that thehydraulic liquid cannot leak out. A steel core 3 extends through thecenter of the two housing plates as well as through the plates 2 and thepress space.

As shown in FIG. 1, the flexible ram 8 coaxially surrounds the ringspace which is bound on the upper and lower side by the plates 2. Theflexible ram 8 extends in length between the two parallel plates 2. Theram 8 is also coaxially surrounded by a flexible pressure membrane 7which extends axially between the upper and the lower housing plates 1,thereby providing a seal against the pressure medium 5, for examplehydraulic oil, which is supplied externally via a connection 6.

For fabricating the solidified drug supply, initially the drug materialwhich may be a granulated carrier/active ingredient mixture madepourable by spray granulation or dry force mixing, is introduced intothe press space. After introduction of the drug material into the pressspace, oil pressure is applied to the press (cf. direction of arrow inFIG. 1a), whereby the state shown in FIG. 1a is established.

As is evident from FIG. 1a, the plates 2 do not travel during theextrusion process and therefore do not apply an active pressing force tothe drug material. To the contrary, they absorb the pressing forceapplied radially by the hydraulic media 5 via the pressure membrane 7and the ram 8. By applying the hydraulic pressure concentrically in aradial direction in the direction towards the core 3, the drug materialis densified and a solidified drug supply is generated. During thepressing operation, the ram slides slightly radially inwardly on the endfaces of the upper and lower plate 2, causing the pressing force to thedrug supply 9a to be transmitted exclusively radially and thuseliminating any axial shear movement within the drug supply.

A drug supply created in this fashion has, as a result of theabovedescribed internal friction, a density gradient with an exclusivelyradial orientation, i.e., zones of equal density are arranged paralleland concentrically around the center axis of the drug supply 9a.

At the end of the pressing operation, the oil pressure is lowered, theram 8 and the pressure membrane 7 return to their initial position (FIG.1), and the drug supply shaped in form of a ring tablet 9a is removedafter the mold is opened. Technical details of the press chamber, suchas sealing of the oil charge and the like, are not shown for the sake ofclarity.

The ring-shaped drug supply described above may, for example, have anoutside diameter of 16 mm, an inside diameter of 10 mm, and a height of6 to 60 mm. The drug material may be, for example, a mixture of 7.5%salbutamol in granulated lactose, pressed with a pressure of about 170MPa.

Consequently, the density gradient in axial direction at a bulk densityof 1.317 g/cm⁻³ is not greater than 0.05% and the density gradient inradial direction is not greater than 0.3%, wherein the minimum densityis found approximately in the middle of the wall thickness of the ringtablet. With these properties, a drug supply fabricated by this methodis optimally suited for an aerosol generator as described in theabove-referenced WO 93/24165, since with this device, the particles areremoved from the drug supply by a face cutter operating in axialdirection. Consequently, a very tightly distributed, identicalconcentric density distribution which does not affect the quality orquantity of the aerosol, is encountered across the entire usage region.It is also important that the pressing operation can be carried outwithout any auxiliary pressing means. For example, the ring-shaped drugsupply according to the invention may be simply affixed to the tabletholder of an aerosol generator with cyanoacrylate glue.

It should be restated that the data discussed above and the materials ofthe drug supply are only provided as examples and that the presentinvention can be applied to a variety of drug materials and mixtures,respectively. The term drug here includes any pharmaceuticalcomposition.

What is claimed is:
 1. A solidified drug supply for making inhalabledrug particles through a metering device including a removal means forabrading the solidified drug supply, said drug supply comprising asolidified body of medicament having a substantially uniform radialdensity formed by applying a radial pressing force from outside in adirection toward a core positioned centrally in the solidified body. 2.The drug supply of claim 1 wherein the pressing force is applied in adirection essentially perpendicular to the direction of removal.
 3. Thedrug supply of claim 1 wherein the solidified body has a circular ringshaped cross section.
 4. The drug supply of claim 1 wherein thesolidified body is fabricated from a granulated carrier material-activeingredient mixture.
 5. The drug supply of claim 1 wherein the solidifiedbody is fabricated from a granulated carrier material-active ingredientmixture at a pressing force between 50 and 500 MPa.
 6. The drug supplyof claim 1 wherein the solidified body exhibits a radial densitygradient of no more than 0.3% perpendicular to the direction ofabrasion.
 7. The drug supply of claim 1 wherein the solidified bodyexhibits a radial density gradient of no more than 0.05% in thedirection of abrasion.
 8. A process of making a solidified drug supplyfor producing inhalable drug particles by means of a metering deviceincluding a removal unit for abrading the drug supply, said processcomprising the step of applying from outside a pressing force onto amedicament material in a direction toward a core positioned centrally inthe medicament material resulting in a substantially uniform radialdensity of the solidified drug supply.
 9. The process of claim 8, andfurther comprising the step of pre-shaping the medicament material intoa body of medicament prior to said force applying step.
 10. The processof claim 9 wherein the body of medicament is pre-shaped in the form ofan annulus.
 11. The process of claim 8, and further comprising the stepof removing the core after the force applying step.
 12. The process ofclaim 9 wherein the body of medicament is made from a rod-shaped body byseparating a piece of suitable length in a direction perpendicular to alongitudinal extent of the rod-shaped body.
 13. Apparatus for making asolidified drug supply, comprising:a press having at least twostationary plates in spaced-apart and parallel disposition and aflexible ram, said plates and said ram having inner surfaces orientedperpendicular to one another as to form a medicament material receivingchamber; a core positioned centrally in the chamber; a pressure sourcefor supplying a medium under pressure; and a pressure-transmitting meanspositioned at a core-distal side of the ram and acted upon by the mediumunder pressure to move the ram in a direction of a core, therebycompacting the medicament material.
 14. The apparatus of claim 13wherein the pressure-transmitting means is a flexible membrane whichslides radially inwardly on confronting end faces of the plates, therebyensuring application of only a radial pressing force onto the medicamentmaterial.
 15. The process of claim 8 wherein the pressing force has asame magnitude across the entire outside surface of the medicamentmaterial.